Significance Of Ghrelin In Nonalcoholic Fatty Liver Diseasa And Its Intervention

Objective: Ghrelin is a 28 amino acids polypeptide,widely distributed in the peripheral and central nervous system.It has two forms: acylated ghrelin(AG)and unacylated ghrelin(UAG).AG can induce food intake and obesity and increase insulin level,while UAG seems to antagonize the effect of AG,which is speculated to participate in the pathogenesis of non-alcoholic fatty liver disease(NAFLD).However,there rare animal studies to our knowledge.Therefore,the changes of ghrelin in the NAFLD was studied and the effect of peripheral and central administration of ghrelin receptor inhibitor [D-Lys-3]-GHRP-6 on NAFLD and its underlying mechanisms were explored in our present study.Methods: NAFLD rat model was established by feeding high-fat–highcholesterol and intervened peripheral and central administration of [D-Lys-3]-GHRP-6.The levels of total cholesterol(TC),triglyceride(TGs),high density lipoprotein cholesterol(HDL-C),low density lipoprotein cholesterol(LDL-C),alanine amino transferase(ALT)and aspartate amino transferase(AST)in serum and liver TGs were measured by colorimetry;rat liver pathology was observed by HE staining;rat plasma total ghrelin(TG),UAG,and AG were determined by RIA;the changes of AG and GHR-1a in the hypothalamus were determined by RT-PCR and Western blot,respectively;the expressions of AG and its receptor in the arcuate nucleus and lateral hypothalamic area were observed by immunohistochemistry;the changes of serum adipokines and HOMA-IR were measured by ELISA;the expression of insulin signaling pathway factors PI3 K,p-PI3 K,Akt,p-Akt,mTOR and p-mTOR in rat liver and hypothalamus were determined by Western blot.Results: Compared with the control group,serum lipid and transaminase and hepatic TGs levels in the model group were significantly increased(P<0.05-0.01),in combination with hepatic steatosis and hepatic lobular disorder,which indicated a successful establishment of NAFLD model.Plasma TG and UAG were significantly decreased while hypothalamic AG and GHSR-1a expressions were increased in the model group(P<0.01).The levels of resistin and leptin were significantly increased(P<0.05-0.01)while adiponectin was significantly decreased(P<0.01)in the model group.Plasma UAG was negatively correlated with LDL-C,hepatic TGs,HOMA-IR and leptin,while positively correlated with adiponectin;plasma TG was negatively correlated with TG,LDL-C,hepatic TGs and leptin,while positively correlated with adiponectin;plasma AG was positively correlated with HOMA-TR;Plasma UAG/AG was negatively correlated with LDL-C,hepatic TGs and HOMA-IR,while positively correlated with adiponectin.The expression of AG and GHSR-1a in hypothalamus was positively correlated with hepatic TGs and HOMA-IR.Compared with the model group,the levels of TC,TGs,LDL-C,liver TGs,ALT and AST in serum were significantly decreased(P<0.05-0.01),HDL-C levels were significantly increased(P<0.05),liver pathological damage was alleviated and HOMA-IR levels were decreased(P<0.05-0.01)after peripheral and central administration of [D-Lys-3]-GHRP-6.Compared with the model group,the expression levels of p-PI3 K,p-Akt and p-mTOR in the liver of rats were significantly increase in the peripheral [D-Lys-3]-GHRP-6 treatment group(P<0.01);the expression levels of p-PI3 K,p-Akt and pmTOR in the hypothalamus of rats were significantly increased in the central [D-Lys-3]-GHRP-6 treatment group(P<0.01).Conclusions: The decrease of circulating UAG/AG,other than the UAG or AG alone,combined with hypothalamic AG and GHSR-1a over-expression,is possibly associated with hepatic lipid deposit and insulin resistance(IR),so as to participate in the pathogenesis of NAFLD.Both peripheral and central administration of [D-Lys-3]-GHRP-6 can activate insulin signaling pathway factors.improve insulin resistance and exhibited an intervention effect on NAFLD in rats.The above results provide a reference for the discovery of [D-Lys-3]-GHRP-6 as a new therapeutic target for NAFLD drugs.